Impairment of cholinergic-dopaminergic interaction are a prominent feature in drug abuse. Imbalance in either the cholinergic or dopaminergic system automatically affects the other system and inevitably leads to impaired perception, motor control and/or cognition. We propose to examine the neuronal circuits, synaptology and types of receptors involved in ACh-DA interactions in the cerebral cortex and in the mesencephalon and basal forebrain systems that innervate the cerebral cortex. Specific Aim #1 focuses on the chemical neuroanatomy of cholinergic influence on the mesencephalic dopamine system of neurons and explores, among other issues, the possibility that DA transmission is influenced by particular nicotinic receptor subunits. Specific Aim #2 addresses the converse relationship, i.e., the dopaminergic inputs to the basal forebrain cholinergic cortical projecting neurons and the localization of dopaminergic D1/D5 receptors on these neurons, as an indirect mechanism for explaining ACh release in cortex induced by D1 agonists. Finally, in Specific Aim #3, we propose to examine the direct and indirect interplay of the two systems in the cerebral cortex where each is known to influence and modulate the cognitive processes that are impaired/accentuated by drugs of abuse. As will be detailed in Background, the ascending circuitry of the brain stem DA system has recently been shown to differ from that of the rodent and some of the questions that will be addressed in this project arise from this difference. Further, the expansion and differentiation of cerebral cortex in primates is an opportunity to illuminate the substrates of drug action that may be regionally and functionally specialized. We have the necessary experience in the principal methods of light and electronmicroscopic immunohistochemistry independently and in combination with retrograde tracing and have previously successfully delineated features of cortical and subcortical synaptic architecture in the primate brain. The subtype specific antibodies against dopamine receptor fusion proteins developed at Yale and antibodies to alpha and beta nicotinic subunits needed to carry out the proposed research are also available to us. Only by knowledge of the dopamine-cholinergic synaptic interactions at several major levels of the neuroaxis will it be possible to obtain a comprehensive picture of systemic drug influence, including that of drugs of abuse, on behavior.